Human antibodies that bind cd70 and uses thereof

Abstract

The present disclosure provides isolated monoclonal antibodies that specifically bind to CD70 with high affinity, particularly human monoclonal antibodies. Preferably, the antibodies bind human CD70. In certain embodiments, the antibodies are capable of being internalized into CD70-expressing cells or are capable of mediating antigen dependent cellular cytotoxicity. Nucleic acid molecules encoding the antibodies of this disclosure, expression vectors, host cells and methods for expressing the antibodies of this disclosure are also provided. Antibody-partner molecule conjugates, bispecific molecules and pharmaceutical compositions comprising the antibodies of this disclosure are also provided. This disclosure also provides methods for detecting CD70, as well as methods for treating cancers, such as renal cancer and lymphomas, using an anti-CD7Q antibody of this disclosure.

1 . An antibody-partner molecule conjugate comprising an isolated human monoclonal antibody, or an antigen-binding portion thereof, wherein the antibody binds human CD70 and exhibits at least one, two, three, four, five, or all six of the following properties:
 (a) binds to human CD70 with a K D  of 1×10 −7  M or less; and   (b) binds to a renal cell carcinoma tumor cell line;   (c) binds to a lymphoma cell line;   (d) is internalized by CD70-expressing cells;   (e) exhibits antibody dependent cellular cytotoxicity (ADCC) against CD70-expressing cells; and   (f) inhibits growth of CD70-expressing cells in vivo when conjugated to a cytotoxin, and a partner molecule, wherein the partner molecule is a therapeutic agent.   
     
     
         2 .- 9 . (canceled) 
     
     
         10 . The antibody-partner molecule conjugate of  claim 1 , wherein the monoclonal antibody, or antigen binding portion thereof, binds an epitope on human CD70 recognized by a reference antibody, wherein the reference antibody comprises:
 (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:7;   (b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:2 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8;   (c) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:3 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:9;   (d) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:4 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:10;   (e) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:5 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:11;   (f) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:73 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:11; or (g) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:6 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:12, and a partner molecule, wherein the partner molecule is a therapeutic agent.   
     
     
         11 .- 17 . (canceled) 
     
     
         18 . An antibody-partner molecule conjugate comprising an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product of or derived from a human V H  3-30.3 gene, human V H  3-33 gene, human V H  4-61 gene, or human V H  3-23 gene, and a light chain variable region that is the product of or derived from a human V K  L6 human V K  L15 gene, human V K L6gene, or human V K  A27 gene, wherein the antibody specifically binds CD70, and a partner molecule, wherein the partner molecule is a therapeutic agent. 
     
     
         19 .- 20 . (canceled) 
     
     
         21 . The antibody-partner molecule conjugate of  claim 1 , wherein the antibody or antigen-binding portion thereof, comprises:
 (a) a heavy chain variable region CDR1 comprising SEQ ID NO:13;   (b) a heavy chain variable region CDR2 comprising SEQ ID NO:19;   (c) a heavy chain variable region CDR3 comprising SEQ ID NO:25;   (d) a light chain variable region CDR1 comprising SEQ ID NO:31;   (e) a light chain variable region CDR2 comprising SEQ ID NO:37; and   (f) a light chain variable region CDR3 comprising SEQ ID NO:43, or   (a) a heavy chain variable region CDR1 comprising SEQ ID NO:14;   (b) a heavy chain variable region CDR2 comprising SEQ ID NO:20;   (c) a heavy chain variable region CDR3 comprising SEQ ID NO:26;   [d) a light chain variable region CDR1 comprising SEQ ID NO:32;   (e) a light chain variable region CDR2 comprising SEQ ID NO:38; and   (f) a light chain variable region CDR3 comprising SEQ ID NO:44, or   (a) a heavy chain variable region CDR1 comprising SEQ ID NO:15;   (b) a heavy chain variable region CDR2 comprising SEQ ID NO:21;   (c) a heavy chain variable region CDR3 comprising SEQ ID NO:27;   (d) a light chain variable region CDR1 comprising SEQ ID NO:33;   (e) a light chain variable region CDR2 comprising SEQ ID NO:39; and   (f) a light chain variable region CDR3 comprising SEQ ID NO:45; or   (a) a heavy chain variable region CDR1 comprising SEQ ID NO:16;   (b) a heavy chain variable region CDR2 comprising SEQ ID NO:22;   (c) a heavy chain variable region CDR3 comprising SEQ ID NO:28;   (d) a light chain variable region CDR1 comprising SEQ ID NO:34;   (e) a light chain variable region CDR2 comprising SEQ ID NO:40; and   (f) a light chain variable region CDR3 comprising SEQ ID NO:46; or   (a) a heavy chain variable region CDR1 comprising SEQ ID NO:17;   (b) a heavy chain variable region CDR2 comprising SEQ ID NO:23;   (c) a heavy chain variable region CDR3 comprising SEQ ID NO:29;   (d) a light chain variable region CDR1 comprising SEQ ID NO:35;   (e) a light chain variable region CDR2 comprising SEQ ID NO:41; and   (f) a light chain variable region CDR3 comprising SEQ ID NO:47 or   (a) a heavy chain variable region CDR1 comprising SEQ ID NO:17;   (b) a heavy chain variable region CDR2 comprising SEQ ID NO:23;   (c) a heavy chain variable region CDR3 comprising SEQ ID NO:75;   (d) a light chain variable region CDR1 comprising SEQ ID NO:35;   (e) a light chain variable region CDR2 comprising SEQ ID NO:41; and   (f) a light chain variable region CDR3 comprising SEQ ID NO:47 or   (a) a heavy chain variable region CDR1 comprising SEQ ID NO:18;   (b) a heavy chain variable region CDR2 comprising SEQ ID NO:24;   (c) a heavy chain variable region CDR3 comprising SEQ ID NO:30;   (d) a light chain variable region CDR1 comprising SEQ ID NO:36;   (e) a light chain variable region CDR2 comprising SEQ ID NO:42; and   (f) a light chain variable region CDR3 comprising SEQ ID NO:48.   
     
     
         22 .- 27 . (canceled) 
     
     
         28 . An The antibody-partner molecule conjugate of  claim 1 , wherein the isolated monoclonal antibody, or antigen binding portion thereof, comprises:
 (a) a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-6, and 73; and   (b) a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 7-12;   wherein the antibody specifically binds a human CD70 protein, and a partner molecule, wherein the partner molecule is a therapeutic agent.   
     
     
         29 . The antibody-partner molecule conjugate of  claim 28 , wherein the antibody or antigen-binding portion thereof, comprises:
 (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1; and   (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7.   
     
     
         30 . The antibody-partner molecule conjugate of  claim 28 , wherein the antibody or antigen-binding portion thereof, comprises:
 (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2; and   (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8.   
     
     
         31 . The antibody-partner molecule conjugate of  claim 28 , wherein the antibody or antigen-binding portion thereof, comprises:
 (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 3; and   (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 9.   
     
     
         32 . The antibody-partner molecule conjugate of  claim 28 , wherein the antibody or antigen-binding portion thereof, comprises:
 (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 4; and   (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 10.   
     
     
         33 . The antibody-partner molecule conjugate of  claim 28 , wherein the antibody or antigen-binding portion thereof, comprises:
 (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 5; and   (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 11.   
     
     
         34 . The antibody-partner molecule conjugate of  claim 28 , wherein the antibody or antigen-binding portion thereof, comprises:
 (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 73; and   (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 11.   
     
     
         35 . The antibody-partner molecule conjugate of  claim 28 , wherein the antibody or antigen-binding portion thereof, comprises:
 (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 6; and   (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 12.   
     
     
         36 .- 37 . (canceled) 
     
     
         38 . The antibody-partner molecule conjugate of  claim 1 , wherein the therapeutic agent is a cytotoxin or a radioactive isotope. 
     
     
         39 .- 41 . (canceled) 
     
     
         42 . A method of inhibiting growth of a CD70-expressing tumor cell comprising contacting the CD70-expressing tumor cell with the antibody-partner molecule conjugate of  claim 1  such that growth of the CD70-expressing tumor cell is inhibited. 
     
     
         43 . The method of  claim 42 , wherein the CD70-expressing tumor cell is a renal tumor cell or a lymphoma cell. 
     
     
         44 . The method of  claim 42 , wherein the CD70-expressing tumor cell is from a cancer selected from the group consisting of renal cell carcinoma or lymphoma. 
     
     
         45 . A method of treating cancer in a subject comprising administering to the subject an antibody-partner molecule of  claim 1  such that the cancer is treated in the subject. 
     
     
         46 . The method of  claim 45 , wherein the cancer is a renal cell carcinoma or lymphoma. 
     
     
         47 . The method of  claim 45 , wherein the cancer is selected from the group consisting of: renal cell carcinomas (RCC), clear cell RCC, glioblastoma, non-Hodgkin's lymphoma (NHL), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), Burkitt's lymphoma, anaplastic large-cell lymphomas (ALCL), multiple myeloma, cutaneous T-cell lymphomas, nodular small cleaved-cell lymphomas, lymphocytic lymphomas, peripheral T-cell lymphomas, Lennert's lymphomas, immunoblastic lymphomas, T-cell leukemia/lymphomas (ATLL), adult T-cell leukemia (T-ALL), entroblastic/centrocytic (cb/cc) follicular lymphomas cancers, diffuse large cell lymphomas of B cell lineage, angioimmunoblastic lymphadenopathy (AILD)-like T cell lymphoma, HIV associated body cavity based lymphomas, embryonal carcinomas, undifferentiated carcinomas of the rhino-pharynx, Schmincke's tumor, Castleman's disease, Kaposi's Sarcoma, multiple myeloma, Waldenstrom's macroglobulinemia and B-cell lymphomas. 
     
     
         48 . A method of treating or preventing an autoimmune disease in a subject comprising administering to the subject an antibody-partner molecule of  claim 1  whereby the autoimmune disease is treated or prevented in the subject. 
     
     
         49 . A method of treating or preventing inflammation in a subject comprising administering to the subject an antibody-partner molecule of  claim 1  such that the inflammation is treated or prevented in the subject. 
     
     
         50 . A method of treating a viral infection in a subject comprising administering to the subject an antibody-partner molecule of  claim 1  such that the viral infection is treated in the subject. 
     
     
         51 . The antibody-partner molecule conjugate of  claim 1 , wherein the partner molecule is conjugated to the antibody by a chemical linker. 
     
     
         52 . The antibody-partner molecule conjugate of  claim 51 , wherein the chemical linker is selected from the group consisting of peptidyl linkers, hydrazine linkers, and disulfide linkers. 
     
     
         53 .- 55 . (canceled) 
     
     
         56 . The antibody-partner molecule conjugate of  claim 1 , wherein the antibody, or antigen binding portion thereof, is nonfucosylated. 
     
     
         57 . An isolated monoclonal antibody, or an antigen-binding portion thereof, comprising: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 6 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 12. 
     
     
         58 . An isolated monoclonal antibody, or an antigen binding portion thereof, which binds an epitope on the human CD70 protein recognized by an antibody comprising: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 6 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 12. 
     
     
         59 .- 63 . (canceled)